Method for preparing 4-(3-pyridinyl)-1h-imidazole and the intermediates used

ABSTRACT

The invention concerns a method for preparing compounds of formula (I) wherein R represents a hydrogen atom or an allyl radical containing up to 8 carbon atoms, characterised in that it consists in subjecting a compound of formula (II) wherein alc represents the residue of an alkyl radical containing up to 4 carbon atoms to the action of a compound of formula (III): RCONH2, wherein R retains its previous meaning, to obtain the compound of formula (IV) wherein R retains its previous meaning which is subjected to cyclization to obtain the desired product of formula (I).

This application is a 371 of PCT/FR99/01649 filed Jul. 8, 1999.

The present invention relates to a process for the preparation of4-(3-pyridinyl)-1H-imidazole, of certain of its derivatives as well asthe intermediate products used.

A subject of the invention is a process for the preparation of compoundsof formula (I)

in which R represents a hydrogen atom or an alkyl radical containing upto 8 carbon atoms characterized in that a compound of formula (II)

in which alk represents the remainder of an alkyl radical containing upto 4 carbon atoms is subjected to the action of a compound of formula(III)

RCONH₂  (III)

in which R retains its previous meaning, in order to obtain the compoundof formula (IV)

in which R retains its previous meaning which is subjected to acyclization in order to obtain the sought product of formula (I).

When R represents an alkyl radical, it is for example the methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl or tertbutyl radical.

Alk represents for example a methyl, ethyl or n-propyl radical.

In a preferred embodiment, the reaction between the compounds (II) and(III) takes place in a mixture of alcohol and formamide. As alcoholthere can be mentioned methanol, ethanol or propanol.

The cyclization of the compound of formula (IV) takes place informamide.

A more particular subject of the invention is the preparation of thecompound of formula (I) in which R is a hydrogen atom.

A more particular subject of the invention is a process characterized inthat alk represents a methyl radical.

The cyclization preferably takes place by heating.

4-(3-pyridinyl)-1H imidazole is a known product described for example inJ. Chem.-Soc.-753-5 1938 which can be used for preparing pharmaceuticalproducts (cf. EP 680967).

A subject of the invention is also a process characterized in that theproduct of formula (II) is prepared by the action of an alcohol and ofan alkaline alcoholate, alk₁OH/alk₂OM, alk₁ and alk₂, identical ordifferent, representing an alkyl radical containing up to 4 carbon atomsand M representing a sodium or potassium atom on a compound of formula(A),

OM representing a hydroxyl radical blocked, in the form of a goodparting group in order to obtain 3-(2H-azirin-3-yl) pyridine

which is subjected to the action of an acid in the presence of analcohol alkOH, alk retaining the same meaning as previously in order toobtain the corresponding compound of formula (II)

The oxime is protected for example in the form of mesylate or tosylate,the alcohol and the alkaline alcoholate are for example methanol andsodium methylate, ethanol and sodium ethylate, butanol and sodiumterbutylate.

The acid used can be oxalic acid, formic acid or also hydrochloric orsulphuric acid.

In a preferred embodiment:

M is a tosyl radical

methanol is used in the presence of sodium methylate

the acid is oxalic acid.

A more particular subject of the invention is a process in which alk,alk₁ and alk₂ represent the same alkyl radical for example the methylradical.

A more particular subject of the invention is a process in which theintermediate product 3-(2H-azirin-3-yl)-pyridine is not isolated.

A more particular subject of the invention is a process characterized inthat 1-(3-pyridinyl)-ethanone O-[(4-methylphenyl) sulphonyl] oxime issubjected to the action of methanol and sodium methylate in order toobtain 3-(2H-azirin-3-yl)-pyridine which is subjected to the action ofoxalic acid in order to obtain β,β-dimethoxy-2-(3-pyridinyl)ethyl)-aminewhich is subjected to the action of formamide in order to obtainN-[β,β-dimethoxy-2-(3-pyridinyl)ethyl]-formamide which is subjected to acyclization in order to obtain the sought product.

A quite particular subject of the invention is a process in which theintermediate products used are not isolated.

The compounds of formula (II) with the exception ofβ,β-diethoxy-3-pyridine ethanamine described in Org. Synth. (1986) 64,1926 are new products and are in themselves a subject of the presentinvention.

The compounds of formula (IV) are new and are in themselves a subject ofthe present invention.

A more particular subject of the invention is the compounds of formula(II) and (IV) described in the experimental part namely:

β,β-dimethoxy-3-pyridine ethanamine andN-[β,β-dimethoxy-2-(3-pyridinyl)ethyl]-formamide.

The following examples illustrate the invention without however limitingit.

Preparation: β,β-dimethoxy-3-pyridine ethanamine Stage A:3-[2H-azirin-3-yl)-pyridine

100 g of 1-(3-pyridinyl)-ethanone O-[(4-methylphenyl)sulphonyl]-oxime isintroduced at 20° C. under a nitrogen atmosphere into a solutioncontaining 400 ml of anhydrous methanol and 23.45 g of sodium methylate.Agitation is carried out for 2 hours at 20˜22° C. and a suspensioncontaining the sought product is obtained.

Stage B: β,β-dimethoxy-3pyridine ethanamine

The suspension obtained previously is cooled down to 0° C. and 31.03 gof oxalic acid is added. Agitation is carried out for 15 minutes at0°/+5° C. A suspension is obtained which is used as it is in Example 1.After isolation and purification, β,β-dimethoxy-3-pyridine ethanamine isobtained.

NMR CDCl₃ ppm

1.03(broad m) assumed mobile NH₂

3.02(s)

3.22(s) 6H 2 OCH₃

7.33(bdd, J=5 and 9) H₅

7.80(dt, J=9 and 2) H₄

8.59(dd, J32 5 and 2) H₆

8.73(dd, J=2 and 1) H₂

EXAMPLE 1 4-(3-pyridinyl)-1H-imidazole Stage A₁:N-[β,β-dimethoxy-2-(3-pyridinyl)ethyl]-formamide

100 ml of formamide is added at 60° C. to the suspension prepared above.In this way a suspension is obtained which is used as it is in thefollowing stage. After separation and purification the sought product isobtained.

Stage A₂: 4-(3-pyridinyl)-1Himidazole

7.2 g of β,β-dimethoxy-3-pyridineethanamine in 15 ml of formamide isheated for 5 hours at 80° C. under nitrogen. The reaction mixture ismaintained under agitation at 20° C. for 16 hours. In this way thesought product is obtained.

(Yield=51%).

NMR CDCl₃ ppm

3.24(s) 3.26(s) 6H 2 CH3O

3.55(d, s after exch.) CH₂—NHCO

3.75(d, s after exch.) CH₂—NHCO

5.80(m) mobile H

8.21(m) mobile H

7.32(m) H5

7.64(d, s after exch.) N—CHO

8.00(d, s after exch.) NH—CHO

7.75 to 7.82(m) H₄

8.54(dd) 8.57(dd) H₆

8.68(m) 8.70(dd) H₂

Stage B: 4-(3-pyridinyl)-1H-imidazole

The suspension obtained in Stage A is heated at 125° C. while distillingthe methanol. The reaction medium is maintained under agitation for 16hours. A suspension is obtained which is cooled down to 80° C. and 400ml of demineralized water is added. 130.3 g of oxalic acid is added at80° C. After cooling down to 60 ° C., agitation is carried out for 1hour at 60° C., followed by cooling down to 20° C., agitating for 1 hourat 20° C., cooling down to 0° C., agitating for 16 hours at 0° C.,separating and washing. In this way the oxalate of the sought product isobtained. 4-(3-pyridinyl)-H-imidazole is obtained by the action of asolution of potash.

NMR CDCl₃ ppm

7.38 (dd, J=5 and 8) H₅

7.78(bs) 7.80(bs) H₂′ H₅′

8.12(bd, J=8) H₄

8.41(dd,J=2 and 5) H₆

9.03(bs) H₂

12.36(broad m) mobile H

What is claimed is:
 1. A process for the preparation of a compound ofthe formula

wherein R is hydrogen or alkyl of 1 to 8 carbon atoms comprisingreacting a compound of the formula

wherein alk are individually alkyl of 1 to 4 carbon atoms with acompound of the formula RCONH₂  III to obtain a compound of the formula

and subjecting the latter to cyclization to obtain a compound of formulaI.
 2. The process of claim 1 wherein R is hydrogen.
 3. The process ofclaim 1 wherein alk is methyl.
 4. The process of claim 1 wherein thecyclization is effected by heating.
 5. A process for the preparation ofa compound of the formula

wherein R is hydrogen or alkyl of 1 to 8 carbon atoms comprisingreacting a compound of the formula

wherein M is a hydroxy protective group with an alcohol and analcoholate of the formula alk₁OH and alk₂OM′ alk₁ and alk₂ areindividually alkyl of 1 to 4 carbon atoms and M′ is sodium or potassiumto form 3-(2H-azirin-3-yl)-pyridine, reacting the latter withoutisolation with an acid to form a compound of formula

reacting the latter without isolation with a compound of the formulaRCOHN₂  III to obtain a compound of the formula

and subjecting the latter to cyclization to obtain a compound of formulaI.
 6. The process of claim 5 wherein alk₁, alk₂ are methyl.
 7. Theprocess of claim 5 wherein M is tosyl.
 8. The process of claim 5 whereinthe compound of Formula IV is not isolated.
 9. The process of claim 5wherein 1-(3-pyridinyl)-ethanone-O-[(4-methylphenyl)-sulfonyl]-oxime isreacted with methanol and sodium methylate to form3-(2H-azirin-3-yl)-pyridine, reacting the latter without isolating itwith oxalic acid to obtain β,β-dimethyloxy-3-pyridine-ethanamine,reacting the latter without isolating it with formamide to obtainN-[β,β-dimethoxy-2-(3-pyridinyl)-ethyl]-formamide and subjecting thelatter without isolating it to cyclization by heating to obtain acompound of formula I.
 10. The process of claim 5 wherein cyclization iseffected by heating.